Chronic wounds are non healing wounds that do not follow pathophysiology of ordinary wounds. Chronic wounds are normally stuck in one of the phases of wound healing, usually in the inflammatory phase. The chronic wounds cause significant physical emotional and financial burden on the patients. Chronic wounds may include chronic ulcers, such as venous ulcers, diabetic ulcers, pressure ulcers and burn ulcers.
Diabetic foot problems are among the most serious and costly complications of diabetes. The rising prevalence of diabetes all over the world has brought with it an increase in the number of lower limb amputations performed as a result of the disease. Epidemiological reports indicate that over one million amputations are performed on people with diabetes each year. This amounts to a leg being lost to diabetes somewhere in the world every 30 seconds.
A majority of these amputations are preceded by diabetic foot ulcers (DFU). Only two-thirds of ulcers will eventually heal and the remainder may result in some form of amputation. The median time of healing for an ulcer is approximately six months. Both ulcers and amputations have an enormous impact on people's lives, often leading to reduced independence, social isolation and psychological stress. The diabetic foot is also a significant economic problem, particularly if amputation results in prolonged hospitalization, rehabilitation, and an increased need for home care and social services. In absence of effective, affordable therapies, the current standard of care for the DFU is dressing, keeping the wound clean and off-loading the wound. The only approved treatment available for DFU is in the form of topical gel of platelet derived growth factor, Regranex®. Thus, the treatment options for DFU are limited.
Venous ulcers (or varicose ulcers) are wounds that are thought to occur due to improper functioning of valves in the veins usually of the legs. They are the major cause of chronic wounds, occurring in 70% to 90% of chronic wound cases (Snyder R. J., Clin. Dermatol. 2005, 23: 388-95). It is estimated that venous stasis ulcers affect 500-600,000 people in the United States every year and it is by far the most common type of leg ulcer seen. This type of ulcer accounts for the loss of 2 million working days and incurs treatment costs closing in on $3 billion dollars per year in the USA. Although compression therapy has been the gold standard of treatment of venous stasis ulcers, there are some individuals that cannot tolerate compression over the ulcer; as the pain is just too great. In recent years a drug call pentoxifylline (Trental) has been used with a reasonable amount of success.
Pressure ulcers (PUs), also known as decubitus ulcers, bed sores or pressure sores, are pathomechanically and pathophysiologically induced ischemic-reperfusion injuries that primarily result from unrelieved pressure (Salcido et al., J Spinal Cord Med. 2007; 30:107-116). An estimated 1.3 to 3 million patients in the US have pressure ulcers (PUs); incidence is highest in older patients, especially those who are hospitalized or in long-term care facilities. Aging increases risk, in part because of reduced subcutaneous fat and decreased capillary blood flow. Immobility and comorbidities increase risk further. Annual costs directly related to PU treatment have been estimated to be $3.5 to $7.0 billion a year (Kuhn B A and Coulter S J., Nurs Econ. 1992, 10:353-9). The prevalence of PUs is estimated at 3% to 10% of all hospitalized patients and from 20% to 32% of all elderly hospitalized patients with long-term disabilities (Kosiak M., Arch Phys Med. Rehabil. 1959; 40(2):62-69).
Burn wounds can be caused by various factors like heat, light, electricity, chemicals, etc. The burns depths are described as either superficial, superficial partial-thickness, deep partial-thickness, or full-thickness. About 0.5 million cases are reported every year of burn injuries in US as per the fact sheet “Burn Incidence and Treatment in the United States: 2012 Fact Sheet” (American Burn Association National Burn Repository (2012 report)). Burn injuries are responsible for about 3,000-5,000 deaths per year in the US. The worldwide incidence of fire-related injuries in 2004 was estimated to be 1.1 per 100,000 population, with the highest rate in Southeast Asia and the lowest in the Americas.
A topical treatment for wounds or ulcers is easier to apply and has fewer side effects compared to other routes of administration. In addition, topical drugs having shorter half life have better safety profile than others.
Esmolol hydrochloride is a short-acting beta-1 adrenergic receptor blocker used for treatment or prophylaxis of cardiac disorders in mammals. Esmolol hydrochloride possesses the selective beta-1-adrenergic blocking activity; however, at high concentration it also blocks beta-2-adrenergic receptor. In contrast to conventional beta-blocking compounds, Esmolol hydrochloride contains an ester group leading to its unique short half life of nine minutes.
The presence of ester group in Esmolol makes it prone to degradation due to hydrolysis. This property of Esmolol poses significant challenge in generating its stable formulation. Esmolol hydrochloride is found to be stable around pH of between about 4 and 6, and this is normally achieved by addition of buffers to Esmolol solution. Various formulations of Esmolol hydrochloride have been reported for parenteral administration (U.S. Pat. No. 4,857,552, WO02/076446, U.S. Pat. No. 5,017,609, U.S. Pat. No. 6,528,450, U.S. Pat. No. 6,310,094, WO2008/147715). A topical formulation of Esmolol hydrochloride has not been reported. The present invention provides a topical, dermal formulation that is a tissue adherent thermo-reversible polymeric gel suitable for application on chronic wounds.